Human Bocavirus in Children EDITORIAL BOARD Co-Editors: Margaret C

® CONCISE REVIEWS OF PEDIATRIC INFECTIOUS DISEASES

CONTENTS Human Bocavirus in Children EDITORIAL BOARD Co-Editors: Margaret C. Fisher, MD, and Gary D. Overturf, MD Editors for this Issue: John Bradley Board Members Michael Cappello, MD Charles T. Leach, MD Geoffrey A. Weinberg, MD Ellen G. Chadwick, MD Kathleen McGann, MD Leonard Weiner, MD Janet A. Englund, MD Jennifer Read, MD Charles R. Woods, MD Leonard R. Krilov, MD Jeffrey R. Starke, MD

Human Bocavirus in Children

John C. Arnold, MD

Key Words: human bocavirus (HBoV), new lenges that have led to a slow accrual of younger than 5 years, with the highest rates viruses, respiratory infections, gastroenteritis epidemiologic data. Until recently, there was occurring during winter and early spring. (Pediatr Infect Dis J 2010;29: 557–558) no permissive cell line in which to grow the virus, so the description of “acute infections” DISCOVERY has been limited to detection of viral de- CLINICAL SPECTRUM Human bocavirus (HBoV) was first oxyribonucleic acid (DNA). Such descrip- Although the epidemiologic data detected using nonspecific gene sequencing tions are limited because the presence of show that HBoV is a virus that can be fre- of specimens from human subjects with re- DNA could represent acute infections, pro- quently detected in children and to which an spiratory illness.1 Viral, bacterial, and hu- longed shedding of live virus, or inactive immune response is mounted, its role as a man genetic sequences were identified in 2 virus. In addition, there is no universally pathogen has been controversial. Because libraries of specimens collected at different accepted polymerase chain reaction (PCR) HBoV was first recognized in subjects with times of year. Among the genetic sequences assay for HBoV, which could lead to study- respiratory symptoms, it was suspected to be of many known pathogens was a parvovirus to-study variability in sensitivity and speci- a respiratory pathogen, although proving clone, which was not parvovirus B19. Bo- ficity. While noting the weaknesses of rely- causation has been difficult for 2 reasons. vine parvovirus and canine minute virus ing on nucleic acid detection, most studies of First, the presence of DNA in the airway were the closest genetic relatives to the children have detected HBoV DNA in ap- neither proves that the organism is causing newly discovered parvovirus, and thus, it proximately 5% to 15% of those with symp- disease nor that its tropism is the airway. was called “human bocavirus” (bo for bovine toms of respiratory infection, although a high Second, when a full panel of viral diagnos- and ca for canine). Although HBoV was rate of codetection of other viral pathogens is tics is applied to the sample, other viral initially described with a single genotype, 2 almost universally noted. pathogens are present in approximately 78% 3 closely related variants have subsequently Serologic assays are most often based of samples testing positive for HBoV, with been identified and designated as “HBoV2” on neutralization of viral antigens. Because a common range of 50% to 60% codetections and “HBoV3.” no cell culture system was initially available, described by different investigators. Al- the production of antigen has occurred by though upper respiratory symptoms are fre- EPIDEMIOLOGY cloning structural genes into other expres- quently described in association with HBoV, sion vectors. The selection of the different lower respiratory tract involvement is more Conventional epidemiologic descrip- genes and vectors led to variable rates of variable. HBoV has been detected in 0% to tions of pathogens include surveillance using “seroprevalence.” Insect cell-based antigen 76% of subjects with lower respiratory tract culture to detect acute infections and/or se- production has been used by several investi- illness, with some data suggesting it may be rologic studies to describe previous infec- gators demonstrating HBoV-specific anti- an important factor in asthma exacerbations. tions. HBoV has presented unique chal- bodies in 5% of children 6 months of age and Of course, conclusions about symptoms at- in all samples of children aged 6 to 9 years.2 tributable to HBoV should be tempered by Using similar insect cell-based HBoV anti- the fact that most studies have included a From the Division of Infectious Diseases, Department of body detection, high rates of seroconversion Pediatrics, Naval Medical Center, San Diego, CA. population of subjects recruited solely based The views expressed in this article are those of the in children and persisting antibodies in adults on the presence of such symptoms, which author and do not reflect the official policy or posi- have been verified by multiple investigators. could exaggerate the frequency that a symp- tion of the Department of the Navy, Department of Combined serologic evidence and nu- tom is truly associated with the pathogen. Defense, or the United States Government. cleic acid detection data suggest that children Copyright © 2010 by Lippincott Williams & Wilkins To elucidate the role of HBoV in re- ISSN: 0891-3668/10/2906-0557 are exposed to HBoV relatively frequently. spiratory infections, several studies have DOI: 10.1097/INF.0b013e3181e0747d HBoV detection is most frequent in children compared subjects experiencing respiratory

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The Pediatric Infectious Disease Journal • Volume 29, Number 6, June 2010 www.pidj.com | 557 Concise Reviews The Pediatric Infectious Disease Journal • Volume 29, Number 6, June 2010

symptoms with asymptomatic controls and mens. Because HBoV DNA can be present CONCLUSION present conflicting data. HBoV DNA was each time a child is tested sequentially for HBoV has been most frequently asso- identified in 44/369 (12%) of symptomatic Ͼ4 months after it is first identified, it is not ciated with respiratory, and to a lesser extent, children and 2 of 85 (2%) of the matched known whether the presence of HBoV in gastrointestinal symptoms. The role that 4 controls in one series and in 5% of symp- tonsillar tissue represents persistence, la- HBoV plays as a pathogen has been ques- tomatic children, and none of the asymptom- tency, or prolonged shedding. tioned because of very frequent codetection 5 atic controls in another, suggesting that The lack of permissive cell lines has of other viral pathogens. However, children HBoV is truly a respiratory pathogen. Con- limited the ability to describe the pathogen- with respiratory illness that have higher viral versely, 2 different study groups found no esis of HBoV. Recently, in vitro HBoV in- loads, viremia, seroconversion, and lack of difference in the rates of HBoV detection in fection of pseudostratified epithelial cells other viral pathogens are consistently de- 6,7 symptomatic and asymptomatic children. was accomplished, with confirmation of vi- scribed, suggesting a true role in respiratory 14 It is possible that variability in the age of rus uptake, transcription, and replication. infection. Testing for HBoV is currently lim- study subjects, season, and geographic loca- This model not only helps to support the ited to research settings and no specific treat- tion may have led to such heterogeneity, concept that HBoV is a respiratory pathogen ment is available. although the significance of HBoV in chil- but also allows for detailed analysis of viral dren with and without respiratory symptoms processes and virus/host interactions as well awaits clarification. as the significance of the frequent finding of REFERENCES Early descriptions of the association be- coinfection of HBoV and other respiratory 1. Allander T, et al. Cloning of a human parvovi- tween HBoV in the airway and the presence of pathogens. rus. . .. Proc Natl Acad Sci USA. diarrhea suggested that there may be gastroin- 2005;102:12891–12896. testinal tropism.8 Subsequently, HBoV DNA 2. Endo R, et al. Seroepidemiology of human has been described in up to 9% of diarrheal DIAGNOSIS bocavirus.... J Clin Microbiol. 2007;45: 3218–3223. stools, although other gastrointestinal patho- HBoV is not isolated in standard viral gens are often simultaneously detected. In a 3. Christensen A, et al. Human bocavirus.... in culture cell lines, and there are currently no multiple viral airway infections. J Clin Virol. case-control study, no difference in the rates of commercially PCR or serologic assays avail- 2008;41:34–37. detection of HBoV DNA in stool of children able. In special circumstances, HBoV DNA 9 4. Fry AM, et al. Human bocavirus: a novel parvo- with and without diarrhea was observed. may be identified by a research laboratory, virus. J Infect Dis. 2007;195:1038–1045. HBoV2 is detected more frequently than although the results must be interpreted with 5. Kesebir D, et al. Human bocavirus infection in HBoV in stool, although causality has not been caution given the lack of standardization, young children....J Infect Dis. 2006;194:1276– established. possibility for laboratory contamination, and 1282. HBoV DNA has been detected in im- high rates of codetection of other pathogens. 6. Martin ET, et al. Detection of bocavirus in sa- munocompromised patients with fever, re- A correlation between a high quantitative liva....J Clin Microbiol. 2009;47:4131–4132. spiratory tract illness, hepatitis, gastrointes- viral load and the lack of codetection of other 7. von Linstow ML, et al. Clinical and epidemio- tinal illness, and central nervous system logic characteristics.... Pediatr Infect Dis J. viruses has been described and may be help- 2008;27:897–902. disease, although it is unclear what etiologic ful in identifying HBoV as the causative 10 8. Arnold JC, et al. Human bocavirus....Clin In- role HBoV plays as a sole pathogen in im- pathogen. Although serologic assays are fect Dis. 2006;43:283–288. munocompromised hosts. neither standardized nor commercially avail- 9. Cheng WX, et al. Human bocavirus in chil- able, the presence of HBoV-specific IgM dren....Clin Infect Dis. 2008;47:161–167. PATHOGENESIS along with acute and convalescent anti- 10. Allander T, et al. Human bocavirus and acute HBoV DNA has been most often de- HBoV IgG has been described as a sensitive wheezing....Clin Infect Dis. 2007;44:904–910. 15 tected in the airway and to a lesser extent, the method to detect acute infections. 11. Manning A, et al. Comparison of tissue distribu- stool, suggesting a primary respiratory or tion....J Infect Dis. 2007;195:1345–1352. possibly a gastrointestinal tropism. In addi- 12. Kuethe F, et al. Prevalence of parvovirus B19 and tion, HBoV DNA has also been detected in TREATMENT human bocavirus DNA in the heart.... 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